Emergency Medicine

West Nile Virus: A Mounting Threat

The incidence of this potentially deadly zoonosis has been increasing with each year since it was first reported in the United States in 1999, and cases have been seen in nearly every state. The author provides a backgrounder to help emergency physicians stay prepared for the introduction or reappearance of West Nile virus in their communities.

By James M. Gillard, MD, FACEP, FAAEM

Since the first reported outbreak in the United States in the New York City area in 1999, West Nile virus (WNV) infections have returned every year and have spread to almost every state. In the five years following the initial seven reported deaths in New York, more than 16,000 cases have been reported throughout the country, with at least 660 deaths by 2004. North America was the last continent to be affected by the virus, which spread throughout Africa, Asia, Europe, and Australia after it was first isolated in Uganda in 1937.

About 80% of humans infected with WNV show no clinical symptoms, but the remaining 20% become ill with West Nile fever. A potentially fatal neuroinvasive form of the disease occurs in about 1% of those infected.

The actual number of cases of WNV today is probably much higher than recognized because West Nile fever mimics many other self-limiting febrile illnesses. Another reason for the likely underestimation of the disease’s incidence is that blood samples usually have to be sent to a central laboratory for confirmation of the presence of the virus, and it takes several days to get the results. This is something not frequently done in an emergency department setting for patients who are going to be sent home. However, new diagnostic tests that can be performed in hospital laboratories within 15 minutes are becoming available.

Because WNV is returning each year with increasing frequency, emergency medicine practitioners need to be well informed on its epidemiology, pathology, clinical presentation, and diagnosis, as well as appropriate treatment and preventive measures.

ZOONOTIC DISEASE

West Nile virus causes a zoonotic disease, which means it is a disease of animals (in this case, birds) that can be secondarily transmitted to humans. However, humans are not the only secondary species affected. Pets, wildlife, and livestock may also become ill with the virus.

More specifically, WNV is an arthropod-borne virus, or arbovirus, of the family Flaviridae. These are single-stranded RNA viruses related to other encephalitis-causing viruses in humans. St. Louis encephalitis and Japanese encephalitis are examples of WNV relatives.

West Nile virus shares a common size and spherical symmetry with other Flaviridae viruses. It measures approximately 50 nanometers in diameter and contains a single-stranded RNA consisting of 10,000 to 11,000 bases. This RNA codes for at least 10 proteins, which include the capsid, envelope, and premembrane proteins. The other seven proteins are probably necessary for viral replication. The envelope protein elicits an early antibody response in infected humans. It is the IgM antibody directed against this antigen that is used in at least three newly available diagnostic tests for the disease.

The mosquito is the primary vector for transmission of WNV from birds to humans, although some parasitic flies and ticks can also pass on the disease. Of the 2500 species of mosquitoes in the world, about 43 can carry the virus in their salivary glands. The mosquitoes that probably account for the most WNV infections belong to the genus Culex; other known carriers are of the genus Aedes. Members of the genus Culex range from central Canada through the continental United States and south to Mexico. They are usually attracted to birds but will attack humans during their breeding season. Since birds serve as the primary reservoir for the disease and many birds migrate long distances, it is easy to see how this disease has spread around the world.

LIFE CYCLE OF THE MOSQUITO

Most species of mosquitoes have a similar life cycle. They lay their eggs in standing water, and the eggs take only hours to hatch into larvae. The swimming larvae breathe air through a small tube just below the water’s surface. After about 10 days and four larval stages, an adult mosquito emerges. Mating quickly takes place. The female then finds a blood meal for the nourishment needed to begin laying eggs. Male mosquitoes feed on nectar and do not bite animals; females can feed on nectar sugars but need the blood proteins for reproduction. Most female mosquitoes have a life span of three weeks to several months, depending on their species and environmental conditions. Some species may survive the winter if they find a place to hibernate that is warm enough.

Within the bird reservoir for WNV, the disease is passed by mosquitoes. It is also passed orally between birds through saliva, feces, and possibly direct contact. Predatory birds can get the virus through eating other birds, mosquitoes, or small mammals carrying the disease. Humans, pets, and livestock are usually considered a dead end for propagation of the disease and not a competent reservoir. The disease can be passed between humans through a blood transfusion but not by the handling of infected birds.

Although several hundred bird species have tested positive for WNV, only a few species are considered competent reservoirs for the disease. This competency is based on three factors: how susceptible the species is to getting the disease, how easy it is for the vector to be infected from feasting on that bird’s blood, and how long the virus circulates in the bird’s blood before being neutralized by the immune system. Blue jays, common grackles, house finches and sparrows, and American crows appear to be the most competent. Crows seem to have the greatest mortality. Chickens and pigeons are not considered competent, although they will become seropositive after contact with the virus. Local governmental health agencies may use sentinel chickens or pigeons, placed in areas of suspected infected mosquito populations, to monitor the disease.

It is important to remember that just because the virus is present, an epidemic does not necessarily take place. Many factors must come together. A competent, infected reservoir is needed, as well as the correct vector, various specific environmental conditions, and susceptible humans. Only 20% of infected humans actually become ill.

PATIENT PRESENTATION

West Nile fever is characterized by headache, fatigue, weakness, acute fever, muscle aches, and sometimes a faint macular rash on the trunk and extremities. Eye pain from chorioretinitis is a frequent finding. Rarely, there can be hepatitis, pancreatitis, or myocarditis associated with the disease. The onset of illness can begin from a few days to almost two weeks after the infected mosquito bite. Muscle weakness and fatigue can last more than a month. In contrast to the more serious neuroinvasive form of the disease, West Nile fever is self-limiting. Since so many other diseases may produce similar symptoms, the history and environmental conditions must be carefully assessed to make a presumptive diagnosis.

As noted earlier, WNV neuroinvasive disease is a serious illness that develops in about 1% of infected individuals. In these patients, encephalitis or aseptic meningitis will occur. Symptoms may range from mild confusion to coma and death. Tremors are sometimes reported. In about 13% of patients with neuroinvasive disease, spinal motor neurons of the anterior horn become invaded. An asymmetric flaccid paralysis resembling poliomyelitis has been described. Infection of the brainstem with respiratory paralysis, similar to Guillain-Barré syndrome, may occur, but it is rare. In contrast to West Nile fever, many survivors of the neuroinvasive form of the disease may have permanent deficits.

The risk of developing neuroinvasive disease is known to be higher in elderly patients and organ transplant recipients. Hypertension, malignancies, diabetes, and a compromised immune system most likely add to the risk. There might even be a genetic predisposition to developing severe disease that allows the virus to enter the central nervous system (CNS).

PHYSICAL EXAM AND LAB STUDIES

Physical examination and routine laboratory studies cannot differentiate WNV infections from many other viral illnesses. Specific tests, however, are available for WNV. Some of these tests are complicated and cumbersome, while others are relatively simple. Some tests will cross-react with other flaviviral infections, such as dengue fever. To understand how to interpret specific laboratory tests for this disease, it is important to know the timing of the sequence of events in the infectious process.

After an infected mosquito bites a human, the virus is thought to replicate within the tissues at the site of the bite. The virus spreads to the lymphatics and then on to the bloodstream. It is usually detectable in the blood by the second day of infection, which is about two days before the onset of symptoms, and remains detectable for about a week. Tests for the RNA sequence, called nucleic acid amplification tests (NATs), will detect acute infection only during the viremic stage of the disease. These tests are extremely specific for the virus but not very sensitive, since the virus is cleared from the blood early in the illness. They are important, however, for screening donor blood before transfusion or testing tissue samples.

A positive NAT confirms the presence of the virus and the danger of transmission. The presence of antibodies against the virus in donor blood does not necessarily mean that it is infectious.

A WNV-specific IgM antibody appears in the blood about a week into the infection; it remains detectable for at least two months and sometimes can persist for a full year. An IgG antibody is produced later and persists indefinitely. The detection of this antibody indicates past infection and immunity, but it is a poor marker of acute infection. IgG antibody tests cannot easily differentiate WNV from dengue, St. Louis encephalitis, Japanese encephalitis, or yellow fever. A complicated test called the plaque reduction neutralization test has been used to confirm WNV infections. In this test, live viral cultures are subjected to serum samples at varied concentrations. Inhibition of plaque formation is a positive result. Changes in titers over a period of two weeks confirm acute infection. Unfortunately, this test may crossreact with other flaviviruses.

IgM antibodies usually do not get into cerebral spinal fluid (CSF) because of their large size. They can be found in CSF during inflammation, however. The presence of a WNV-specific IgM in CSF confirms neuroinvasive disease. It is important to know that the serum IgM is usually detectable by the time of the onset of CNS symptoms.

What is different about this season in terms of WNV infections is the availability of new diagnostic tests. In 2002, the FDA approved a transcription-mediated amplification test from Gen-Probe that detects the RNA sequence of the WNV in banked blood and tissues. Inbios received approval for an IgM enzyme-linked immunosorbent assay (ELISA) in 2004. PanBio and Focus Technologies both received approval for their IgM capture ELISA assays in 2003. Spectral Diagnostics received approval in 2005 in Canada to market their WNV lateral flow IgM capture test. This test is unique in that it is run on a disposable point-of-care platform with diluted serum in 15 minutes. Its FDA approval in the United States is pending.

NO SPECIFIC TREATMENTS

For humans, there are no specific treatments for WNV infections. There are small studies showing some promise in the use of human immunoglobin in immunocompromised patients dying of the disease, but this is only experimental. Ribavirin and interferon are also being considered for possible future treatments. Unfortunately, there is no vaccine available for humans yet. Horses have a 30% to 40% mortality with WNV infections, and there are two commercially available equine vaccines. So far, however, these vaccines have not been used long enough to fully judge their effectiveness.

Mosquito bite prevention is the most powerful weapon against WNV infections. Standing water in mosquito breeding areas needs to be drained or treated. The use of insect repellents is recommended in areas with mosquito populations. The introduction of mosquito larva-eating fish in ponds has resulted in marked decreases in mosquito populations.

Insect repellants like DEET (N, N-diethyl-m-toluamide) and picaridin are recommended to prevent bites. These products do not repel mosquitoes; they block the insect’s ability to smell carbon dioxide, the substance mosquitoes use to locate their prey. DEET and picaridin are the active ingredients in many commercially available products. Oil of lemon eucalyptus (also known as p-menthane 3,8-diol, or PMD), a plant-based mosquito repellent, works in the same manner and is also effective.

Permethrin is another ingredient in repellents marketed for use on clothing. This compound is actually a powerful insecticide, with low toxicity in humans. When used on the skin, it is rapidly deactivated by esterases, but it has a long duration of action when applied to clothing. It is similar in structure to pyrethrum, a naturally occurring insecticide found in chrysanthemums. It will quickly kill mosquitoes that come in contact with it by attacking their nervous system. Permethrin can remain in clothing fibers for weeks.

There is no question that WNV infections are becoming more frequent almost everywhere in North America. Increased encounters with the disease, along with new diagnostic tests, will undoubtedly make the diagnosis easier for the emergency medicine practitioner. However, at this time, prevention remains the most important factor in the control of WNV.